A Single Adulteration Limit for Cleaning Validation in a Pharmaceutical Pilot-Plant Environment

A well run cleaning-validation program requires a significant amount of planning and resources. Planning takes into account the size, configuration, and complexity of the manufacturing equipment; the physical properties of the soils encountered, which directly affect the cleaning procedure used; the detergent to clean the equipment; the type of swab or rinse sampling to capture residue levels; the analytical test methods to determine residue levels; the periodic monitoring of the system to ensure ongoing compliance; change control to address new residues and equipment; appropriate documentation; and training for personnel cleaning equipment and performing validation challenges. Required resources include equipment downtime for the validation, raw materials for the formulations tested, analytical instrumentation for analysis, detergents for cleaning, solvents for testing, and personnel to perform the validation.

The entire cleaning-validation program and its execution depend directly on the acceptable residue limit (ARL) for the formulation residue. The active pharmaceutical ingredient (API) residue is monitored because it is the most phamacologically active component of the formulation. The ARL established for a program must be scientifically justified on the basis of the needs and capabilities of the manufacturing facility. In its Guide to Inspection of Validation of Cleaning Processes (1), the US Food and Drug Administration stated that residue limits should be logical, practical, achievable, and verifiable. The agency did not intend to set acceptance limits for validating cleaning processes. One of the examples cited as a possible residue limit used in industry, however, was 10 ppm of carryover into the subsequent batch manufactured.

The purpose of cleaning validation is to prevent the cross-contamination of a drug formulation. The primary concerns of cross-contamination are an evaluation of the therapeutic-dose carryover or the toxicity of the potential contaminant. Any contaminant is undesirable, but one with a pharmacologic or toxicological effect is far more serious. The Food, Drug, and Cosmetic Act (2) states: "A drug ... shall be deemed to be adulterated if it consists in whole or in part of any filthy, putrid, or decomposed substance," that is, something that will cause an adverse pharmacological effect. This definition supports the pharmacological and toxicological concerns.

If, however, the amount of a residue is below the level at which it would have an unintended, adverse health effect, what is the allowable level from an adulteration standpoint? Should a health-based limit be the only limit for equipment cleaning? Should the analytical-method detection limit be the standard (3)? Or, if an intermediate adulteration limit exists, what rationale determines that level? In the past, analytical methodology had limited sensitivity, making health-based and adulteration-based contaminations essentially equivalent. The increased sensitivity of analytical methodology seemingly has created a contradictory situation. Modern analytical detection limits are far lower than the pharmacological levels of drugs, thus creating a divergence between the previously equivalent health-based and adulteration definitions.

A logical residue limit would be one that demonstrates no pharmacological or toxicological effect, without regard to analytical sensitivity. This would indicate that residue levels can be as high or as low as the health-based limit will allow. This approach, however, would allow equipment to be visually dirty for relatively safe residues, which indicates an inadequate cleaning procedure. A logical residue limit also should leave the equipment visually clean. Setting residue limits any lower than the health-based and visible levels does not appear to be necessary or logical and adds no additional value to the cleaning process.

Several cleaning-validation programs use the dual health-based–adulteration-based criterion (4–6). Evaluations based on toxicity, tablet weight, number of doses administered, swab recovery, swab area or equipment surface area, and batch size determined the ARLs from both an adulteration-based and health-based perspective. The lower of the two limits was the designated ARL for the formulation and the equipment.

The cleaning-validation program in our pilot-plant facility calculated ARLs for both the health-based and adulteration-based criteria and used the lower of the two (7). The dynamic nature of the pilot plant and the drug-development process necessitated regular re-evaluation of the ARL for each API. Each API required a health-based evaluation, but the majority of development compounds had such low toxicity that their adulteration limits were lower. A proposed alternative to the constant re-evaluation of adulteration limits was to use a constant adulteration limit of 100 μg/25 cm2 swab or 4 μg/cm2 . This technique would streamline the cleaning process and minimize potential errors without compromising quality or safety.